Diarrhealdiseasesareamajorcauseofinfantmortalityworldwideandareusuallytheresultofinadequateaccesstocleanfoodandwater.Evenindevelopedcountries,diarrhealdiseasescausesubstantialsufferingandoccasionalwell-publicizeddeathsandcarryasubstantialeconomicburdenbecauseoftheirprevalence.Infectiousdiarrheaiscausedbyanumberoforganisms,withseveral(e.g.,choleraorpathogenicstrainsofEscherichia coli)capableofelaboratingtoxinsthattriggerexcessiveincreasesinactiveCl− secretionbysmallandlargeintestinalepithelialcells.Diarrheacanalsoresultwhennutrientsarenotappropriatelydigestedandabsorbedinthesmallintestine(e.g.,lactoseintolerance)orasaresultofcolonicinflammation.Inmostdiarrhealdiseases,colonicNaClandNa+ absorptionaredownregulatedatthesametimeCl− secretionmaybestimulated,thusfurtherworseningfluidloss.Ontheotherhand,nutrient-linkedNa+ absorptiveprocessestypicallyremainintact.Thisprovidestherationalefortheeffectivenessoforalrehydrationsolutions,whichareprepackagedmixturesofsaltandglucose.UptakeofNa+ andglucosefromthesesolutions,mediatedbySGLT1(see ),restoresfluidabsorption.Thesesolutionssavelivesinareaswherediarrheaisprevalentandtheabilitytorehydratepatientswithsterileintravenoussolutionsislimitedorabsent.
The colonic microbiota is not essential to life because animals raised in germ-free conditions apparently develop normally and are able to reproduce. However, in such animals the mucosal immune system is immature, and intestinal epithelial cells differentiate more slowly. Importantly the colonic microbiota provides benefits to the host in that the constituent microbes are capable of performing metabolic reactions that do not take place in mammalian cells. Bacterial enzymes act on both endogenous and exogenous substrates. They form secondary bile acids and deconjugate bile acids that have escaped uptake in the terminal ileum, so they can be reabsorbed. They convert bilirubin into urobilinogen (see ) and salvage nutrients that are resistant to pancreatic and brush border hydrolases, such as dietary fiber. A summary of the metabolic contributions of the colonic microbiota is provided in
Table 31.1 . Microbial metabolism can also be exploited for pharmacological purposes. A drug targeted to the colon, for example, can be conjugated in such a way that it will become bioavailable only after it is acted on by bacterial enzymes. Bacterial enzymes may also detoxify some dietary carcinogens, but equally they may generate toxic or carcinogenic compounds from dietary substrates.
Commensal microorganisms also play a critical role in limiting the growth or invasion (or both) of pathogenic microorganisms. They fulfill this antimicrobial role via a number of different mechanisms—by synthesizing and secreting compounds that inhibit the growth of competitor organisms or that are microbicidal, by functioning as a physical barrier to prevent attachment of pathogens and their subsequent entry into colonic epithelial cells, and by triggering patterns of gene expression in the epithelium that counteract the adverse effects of pathogens on epithelial function. These mechanisms provide a basis for understanding why patients who have received broad-spectrum antibiotics, which temporarily disrupt the colonic microbiota, are susceptible to overgrowth of pathogenic organisms and associated intestinal and systemic infections. They may also shed light on the efficacy of probiotics, commensal bacteria selected for their resistance to gastric acid and proteolysis that are intentionally ingested to prevent or treat a variety of digestive disorders.